Energy
Availability and Alcohol–Related Liver Pathology

Carol
C. Cunningham, Ph.D., and Cynthia G. Van Horn, Ph.D.

Carol
C. Cunningham, Ph.D., is professor of biochemistry, and Cynthia G. Van
Horn, Ph.D., is a postdoctoral fellow, both in the Department of Biochemistry
at Wake Forest University School of Medicine, Winston–Salem, North
Carolina.

The
studies from the authors’ laboratory were supported by National
Institute on Alcohol Abuse and Alcoholism grants AA–02887 and
AA–00279, and by training grant AA–07565 (C.G.V.H.).

Alcohol consumption
alters the metabolism of the most common type of cell found in the liver,
the hepatocyte. The presence of alcohol in the body causes the liver to use
more oxygen—for example, when breaking down the alcohol. Increased oxygen
use, in turn, causes oxygen deficits in several key cells, particularly in
hepatocytes located near the small hepatic veins. These veins return blood
to the heart for re–oxygenation after it has passed through the liver.
Hepatocytes surrounding these veins are the first to show signs of liver disease.
The damage induced by oxygen deficits may be exacerbated by alcohol–induced
deficits in other components that are essential for cell survival. For example,
adenosine triphosphate (ATP), the cell’s main source of energy, is generated
primarily during the course of two sets of metabolic reactions: glycolysis
and the mitochondrial oxidative phosphorylation process. Alcohol consumption
may interfere with both of these pathways of ATP production through several
mechanisms. An inadequate supply of ATP impairs the cell’s ability to
perform critical functions, including the repair of alcohol–induced
cell damage, and may therefore contribute to cell death and alcoholic liver
disease. Key
words: chronic AODE (alcohol and other drug effects); alcoholic liver disorder;
oxygen; bioavailability; energy, liver; hepatocyte; ATP (adenosine triphosphate);
metabolism; mitochondria; glycolysis; oxidative phosphorylation; pathogenesis

A substantial amount of
evidence indicates that alcoholic liver disease develops when alcohol alters
the cellular environment of the liver, thereby initiating abnormal interactions
among various types of liver cells. According to one prominent hypothesis,
alcohol causes changes to the walls of the intestine, which allows a harmful
bacterial product called endotoxin to pass into the blood more readily (Tsukamoto
and Kaplowitz 1996). As a result, endotoxin levels in the blood and tissues
rise. The body responds to this increase in endotoxin by launching a coordinated
immune response. For example, high endotoxin levels in the liver cause immune
cells residing in the liver (Kupffer cells) to release signaling molecules
(i.e., cytokines) as well as other compounds (e.g., prostaglandins) that result
in a stepped–up inflammatory response. (For more information on endotoxin
and its effects on Kupffer cells, see the article in this issue by Wheeler.)
Cytokines and prostaglandins, in turn, increase the metabolic activities of
liver cells, especially the hepatocytes, which account for approximately 90
percent of the liver cell mass. When their metabolism increases, the cells
require more oxygen and fuel (nutrients) to keep pace with this increased
metabolic demand. Oxygen is required for many biochemical reactions in the
cell, and the breakdown of nutrients provides the energy needed for these
reactions. In addition, the breakdown of alcohol itself, which occurs primarily
in the hepatocytes, increases the liver’s need for oxygen, as described
in the next section.

Under normal circumstances
the blood supplies enough oxygen to the liver, but if hepatocytes use up more
oxygen because of the breakdown of alcohol, oxygen deficits (i.e., hypoxia)
can develop in some liver areas. Hypoxia, in turn, may impede the liver cells’
ability to produce an energy–rich molecule called adenosine triphosphate
(ATP), which is generated during the breakdown of nutrients and supplies energy
needed for numerous biochemical reactions. Sufficiently high levels of ATP
are essential to the survival of all cells; reduced ATP levels in the liver
are one factor contributing to liver cell death and may contribute to development
of alcoholic cirrhosis.

This article describes
alcohol’s effects on hepatocyte metabolism and oxygen use, reviewing
the consequences of alcohol–related hypoxia on ATP levels in the liver
and summarizing alcohol’s specific effects on the two main cellular
pathways of ATP production.

Effects of Alcohol Consumption
on Oxygen Use in the Liver

Alcohol consumption can
increase the liver cell’s use of oxygen both indirectly and directly.
The indirect pathway is associated with the alcohol–induced activation
of immune cells (Kupffer cells) that reside in the liver. When Kupffer cells
become activated, they release various signaling and stimulatory molecules,
including prostaglandin E2. This molecule can stimulate the metabolic activity
of the hepatocytes. This metabolic activity consists of breaking down and
synthesizing many essential molecules and cell components, and the chemical
reactions involved in these processes frequently involve oxygen molecules
(i.e., are oxidation and reduction reactions). (For more information on these
reactions, see the sidebar “Oxidation and Reduction Reactions.”)
Thus, more active metabolism in the liver increases the need for oxygen. Animal
studies have yielded results consistent with this scenario, showing that oxygen
use in the liver increases after both acute and chronic alcohol administration
(Yuki and Thurman 1980; Arteel et al. 1996; Videla et al. 1973).

SIDEBAR

Oxidation and Reduction
Reactions

The breakdown of
nutrients such as carbohydrates, proteins, and fats, as well as other
molecules such as alcohol, frequently involves chemical reactions that
use oxygen and/or hydrogen (i.e., oxidation and reduction reactions).
Generally speaking, oxidation reactions are those in which an oxygen
atom is added to a molecule, hydrogen atoms are removed from a molecule,
or electrons are removed from a molecule. (Electrons are the negatively
charged particles in each atom.) In reduction reactions, the reverse
occurs—that is, an oxygen atom is removed or hydrogen atoms or
electrons are added. Oxidation and reduction reactions always occur
together: When, for example, electrons or hydrogen atoms are removed
from molecule A and transferred to molecule B, molecule A has been oxidized,
whereas molecule B has been reduced.

Alcohol (chemically
known as ethanol) is metabolized by several different reactions in the
liver, most of which involve oxidation/reduction reactions (see figure
1 in the main article). The predominant process involves two oxidation
reactions. First, the enzyme alcohol dehydrogenase converts alcohol
to acetaldehyde by removing two electrons. Then, another enzyme, aldehyde
dehydrogenase, converts the acetaldehyde into acetate by removing two
additional electrons, after which a hydroxyl ion from a water molecule
is added (see figure 1). The electrons that are removed during these
reactions are transferred to a molecule called nicotinamide adenine
dinucleotide (NAD), which is thereby converted to reduced NAD (NADH).
NADH can then participate in other metabolic reactions, including reduction
of oxygen to H2O, which is accomplished by the respiratory
chain in the mitochondria. During these reactions, NADH releases its
electrons (another oxidation reaction), becoming available again as
an electron acceptor (see figure 1).

—Carol
C. Cunningham and Cynthia G. Van Horn

END OF SIDEBAR

In addition to these indirect
effects, alcohol directly enhances the liver’s oxygen use through its
own breakdown in the hepatocytes. Alcohol (chemically known as ethanol) can
be broken down with the help of several enzyme systems, including alcohol
dehydrogenase, the cytochrome P450 system, and the fatty acid–catalase
system (Cunningham and Bailey 2001).1 (1 Alcohol dehydrogenase
is located in the fluid filling the cell [i.e., the cytosol]. The cytochrome
P450 system is sequestered within tubular structures in the cell called the
endoplasmic reticulum, and the fatty acid–catalase system is located
in cell structures called peroxisomes.) Each of these systems oxidizes alcohol—that
is, the chemical reaction involved uses oxygen (O2), or removes
electrons from the alcohol molecule or its degradation products, or both (see
figure 1). Of these three systems, the alcohol dehydrogenase system breaks
down most of the alcohol, particularly after moderate alcohol use.

Alcohol dehydrogenase,
together with another enzyme, aldehyde dehydrogenase, breaks down alcohol
to form acetate and water. During this process, electrons are transferred
to a compound called nicotinamide adenine dinucleotide (NAD) to generate reduced
NAD (i.e., NADH) (see figure 1; for more information see the sidebar “Oxidation
and Reduction Reactions”). NADH, in turn, can transfer the newly acquired
electrons to the first of a series of electron transport components composing
the respiratory chain, which is found in a cell structure called the mitochondrion
(Berg et al. 2002). The electrons are eventually transferred to O2,
which then binds protons (H+) to generate water (H2O).
Therefore, cells (i.e., hepatocytes) in which alcohol is oxidized need additional
oxygen, as illustrated in figure 1. (For more information on the respiratory
chain, see the sidebar “Pathways of ATP Production” and the section
“Alcohol–Induced Damage to Liver Mitochondria.”)

Figure 1
Oxygen utilization associated with various pathways of alcohol (ethanol)
oxidation in the liver.

Pathways of ATP
Production

As mentioned in
the main article, a molecule called adenosine triphosphate (ATP) is
the primary source of the energy that is needed for numerous biochemical
reactions in the cell. ATP is formed when nutrients are broken down,
a process that releases energy which then can be used to produce ATP.
One nutrient that is a primary source of ATP production is the sugar
glucose, which either can be imported into the cell from the blood or
generated by the breakdown of glycogen, a large molecule that serves
as a means of storing glucose in the cells. Glucose degradation occurs
in several steps that take place in different areas of the cell (see
the figure). In an initial series of reactions, referred to collectively
as glycolysis, glucose is converted to a molecule called pyruvate. This
process, which occurs in the fluid filling the cell (i.e., the cytosol),
provides enough energy to generate a relatively small amount of ATP
(i.e., two molecules of ATP for each glucose molecule broken down to
pyruvate).

Each step
in the process of metabolizing glucose and generating ATP involves
several biochemical reactions.

The subsequent fate
of the pyruvate depends on the oxygen conditions in the cell. When oxygen
levels are low, pyruvate is converted to lactate, which can accumulate
in the cell; this reaction generates no further ATP. If enough oxygen
is present, however, pyruvate is transported into mitochondria—small
membrane–enclosed cell structures that act as the cell’s
power plants. In the mitochondria, pyruvate enters a chain of biochemical
reactions collectively called the citric acid cycle, which ultimately
degrade pyruvate to carbon dioxide (CO2). During these reactions
(which are called oxidation reactions; see the sidebar on oxidation
and reduction) electrons are released from intermediate reaction products
and transferred to a molecule called nicotinamide adenine dinucleotide
(NAD) to yield reduced NAD (NADH).

NADH can then feed
the electrons into the mitochondrial electron transport system (also
called the respiratory chain). In this electron transport system, the
electrons are released from the NADH and transferred to a series of
other molecules that first accept the electrons and then pass them on
to the next molecule in the chain. Finally, the electrons (together
with protons [H+]) are transferred to oxygen to generate water. These
successive electron transfer reactions provide enough energy to drive
the formation of additional ATP molecules. In fact, the mitochondrial
system generates substantially more ATP than glycolysis, for a total
of 28 ATP molecules for every molecule of glucose (or, more specifically,
two pyruvates) that enters the citric acid cycle. The net result of
all of these reactions is the synthesis of ATP from two precursor molecules,
adenosine diphosphate (ADP) and inorganic phosphate (Pi). This whole
process of ATP production, which is illustrated in the accompanying
figure, requires numerous oxidation and reduction reactions combined
with the reaction of Pi with ADP, and is known as oxidative phosphorylation.

—Carol
C. Cunningham and Cynthia G. Van Horn

END OF SIDEBAR

Together, alcohol breakdown
in the hepatocytes and the indirect effects of alcohol that are mediated by
Kupffer cells cause the liver to use more oxygen than normal during alcohol
consumption. Other mechanisms by which alcohol influences the liver’s
oxygen use probably also exist, but for the processes discussed in this section,
more detailed experimental evidence has been obtained to date.

The alcohol–related
increase in the liver’s use of oxygen exacerbates the normal differences
in oxygen levels found within each of the basic structures, or lobules, of
the liver (Junqueira et al. 1998). The entire liver consists of many thousands
of these lobules, each of which is made up of hundreds of hepatocytes and
other types of cells (see figure 2). Each lobule exhibits the same pattern
of blood flow: Nutrient– and oxygen–rich blood enters the liver
from the portal vein and hepatic artery and is distributed to all the lobules.
Within each lobule, the blood flows past the hepatocytes through small channels
called sinusoids before exiting the lobule through the hepatic venule, a small
vein located in the center of each lobule. As a result, hepatocytes located
near where the blood enters the lobule—that is, close to the portal
vein and hepatic artery (i.e., the periportal hepatocytes)—are exposed
to the most nutrient– and oxygen–rich blood. Liver cells closer
to where the blood exits the lobule at the hepatic venule (i.e., perivenous
hepatocytes) are exposed to blood containing less oxygen because much of the
oxygen and nutrients already has been extracted from the blood by other hepatocytes.
Thus, even under normal metabolic conditions—that is, in the absence
of alcohol—oxygen levels vary in different regions of the liver lobule,
with high concentrations in the periportal cells and lower levels in the perivenous
hepatocytes (see figure 3).

Figure 2
The structure of the liver’s functional units, or lobules. Blood
enters the lobules through branches of the portal vein and hepatic artery,
then flows through small channels called sinusoids that are lined with
primary liver cells (i.e., hepatocytes). The hepatocytes remove toxic
substances, including alcohol, from the blood, which then exits the
lobule through the central vein (i.e., the hepatic venule).

SOURCE: Adapted
from Ross et al. 1995.

Figure 3
The liver lobule in more detail. The blood entering the lobule (at the
hepatic artery, indicated in red) is relatively oxygen rich, but the
blood leaving the lobule contains only low levels of oxygen (at the
terminal hepatic venule, indicated in blue) because hepatocytes along
the sinusoids have used up much of the available oxygen.

When alcohol is consumed
and subsequently broken down in the liver, the oxidation reactions involved
lead to even lower concentrations than normal in the perivenous region of
the lobule (Sato et al. 1983; Arteel et al. 1996). The same region also is
the first to show liver cell death after chronic alcohol consumption (Ishak
et al. 1991), suggesting that an oxygen deficit in this region may be a risk
factor for the development of alcoholic liver disease.

One possible consequence
of this oxygen deficit may be a decrease in the capacity of the perivenous
hepatocytes to produce normal ATP levels that are necessary to the cells’
ability to survive. Researchers have not yet analyzed ATP levels specifically
in the perivenous cells of alcohol consumers; however, they have evaluated
the effect of chronic alcohol consumption on ATP concentrations in the liver
as a whole, as described in the following section.

Alcohol Abuse Reduces
Liver ATP Concentrations

All cells require energy
to fulfill their diverse functions and to ensure the viability of the cells
themselves and the entire organism. This energy is derived from the metabolism
of nutrients, such as carbohydrates, proteins, and fats. When these nutrients
are broken down, energy is released that is used to make ATP, which in turn
can provide the energy to other reactions. Some forms of the nutrients can
be stored in the cells so that they can be broken down to generate ATP whenever
energy is needed for cellular reactions. The ATP itself cannot be stored in
the cells; nevertheless, measuring ATP levels in a tissue provides researchers
with a “snapshot” of the tissue’s metabolic activity and
health.

Oxygen levels in the tissue
(i.e., the oxygen environment) can influence the concentrations of ATP in
the liver, particularly in animals that chronically consume alcohol. For example,
researchers evaluated ATP levels in livers from rats maintained on an alcohol–containing
diet for 1 month and in livers from control animals that did not receive alcohol.
These studies found that when oxygen levels in isolated hepatocytes or larger
sections of the liver were normal, both groups of animals also had normal
ATP levels in their livers. When the cells or tissues had oxygen deficits,
however, ATP levels in the liver were reduced much more dramatically in the
alcohol–consuming than in the control animals (Spach et al. 1991; Bailey
and Cunningham 1999). Other investigators made similar observations with living
animals that had received high doses of alcohol for extended periods of time.
After a period of oxygen deficiency, the livers of alcohol–treated animals
showed greater reductions in ATP levels than did those of control animals
(Miyamoto and French 1988). These findings indicate that chronic alcohol consumption
increases the sensitivity of liver cells to oxygen deficits, resulting in
decreased ATP concentrations in the cells. The results also suggest that ATP
concentrations may decrease in any oxygen–deficient region of the liver
in chronic drinkers, such as the perivenous region of each lobule.

An alcohol–related
reduction in ATP concentrations in the perivenous region might predispose
this area of the lobule to scar tissue formation (i.e., fibrosis) as well
as to cell and tissue death (Ishak et al. 1991). The effects of reduced ATP
levels are particularly dramatic in the livers of alcohol users because ATP
is needed to provide energy for the repair of cell structures and complex
molecules that have been damaged by alcohol or its breakdown products. Alcohol
metabolism gives rise to numerous compounds that are toxic to the cells, including
the following:

Acetaldehyde, which
can interact with proteins and other complex molecules. (For information
on the role of acetaldehyde and other reactive molecules generated during
alcohol metabolism, see the article by Tuma and Casey in this issue.)

Highly reactive, oxygen–containing
molecules collectively called reactive oxygen species (ROS), such as the
hydroxyl radical, superoxide, and hydrogen peroxide. (For more information
on the role of ROS in liver damage, see the article by Wu and Cederbaum
in this issue.)

Other highly reactive
molecules, such as the hydroxyethyl radical, peroxynitrite, and lipid
peroxides.

All of these diverse compounds
react with and damage complex molecules in the cells—such as proteins,
phospholipids (which are central components of the cell membrane), and nucleic
acids (e.g., DNA). The damaged molecules then must be replaced or repaired
to ensure the cell’s survival. These repair processes all require energy.
Consequently, the cells’ demands for ATP increase even further following
chronic alcohol consumption.

Two biochemical pathways
in the cell account for all ATP synthesis. Under normal conditions, most of
the ATP in the liver is generated by a chain of reactions known as the mitochondrial
oxidative phosphorylation system, which is composed of the respiratory chain
and other enzymes. The remaining ATP is produced by the glycolysis pathway,
which consists of a series of chemical reactions involved in the breakdown
of the sugar glucose (Berg et al. 2002). (For more information on these two
pathways, see the sidebar “Pathways of ATP Production.”) It is
well established that chronic alcohol use adversely affects both the structure
and the function of the mitochondria in liver cells, thereby interfering with
the oxidative phosphorylation system. Other evidence indicates that alcohol
also interferes with glycolysis, resulting in reduced ATP synthesis, particularly
in the presence of oxygen deficits. Both of these consequences of chronic
alcohol use are discussed in the following sections.

Alcohol–Induced
Damage to Liver Mitochondria

Most of the cell’s
supply of ATP is generated in mitochondria, which therefore are considered
the cell’s power plants. Researchers found that changes in the structure
and function of hepatic mitochondria are early consequences of chronic alcohol
consumption (Cunningham et al. 1990; Hoek 1994). For example, the mitochondria
can swell to an abnormal size following chronic alcohol consumption. Alcohol
also can change the composition of the phospholipids that make up the mitochondrial
membranes, although it is not known whether these changes influence mitochondrial
functioning. Finally, alcohol can alter the protein content of the mitochondria,
and these alterations interfere with the mitochondria’s ability to synthesize
ATP.

The respiratory chain
consists of a series of proteins that can transfer negatively charged particles
(i.e., electrons) or hydrogen from energy–rich, oxidizable compounds
(e.g., pyruvate generated by the breakdown of the sugar glucose, and fatty
acids generated by the breakdown of dietary fats) to O2 (Berg et
al. 2002). This process releases energy that can be used to generate ATP from
precursor molecules. Mitochondria from the livers of alcohol–fed animals
contain lower amounts of some components of the respiratory chain than do
the mitochondria of control animals (Cunningham et al. 1990). In addition,
the alcohol–fed animals have lower levels of the enzyme complex that
mediates ATP production. As a result, the rate of ATP synthesis in the liver
mitochondria decreases as well, leading to an overall decline in ATP concentration
in the liver.

When oxygen levels in
cells are low, ATP production through the respiratory chain is greatly reduced,
and most ATP is produced through glycolysis (as described in the following
section). Even under those conditions, however, a sufficient amount of oxygen
remains to allow limited mitochondrial synthesis of ATP, at least in healthy
cells. When the cells, and particularly the mitochondria, have been damaged
by alcohol, however, they may not be able to synthesize ATP at the same rate
as normal mitochondria under low–oxygen conditions. To investigate this
possibility, researchers currently are studying whether hepatocytes from alcohol–fed
animals produce lower ATP amounts in their mitochondria. Preliminary results
suggest that when cells from alcohol–consuming animals are maintained
under low–oxygen conditions, ATP production by the mitochondria is significantly
reduced.

Effects of
Chronic Alcohol Consumption on Glycolysis

Glycolysis is a series
of reactions that break down the sugar glucose2 into two molecules
of a compound called pyruvate. (2 Most of the carbohydrates that
are ingested with the diet are first converted to glucose before they undergo
final metabolism.) During glycolysis, which is described in more detail in
the sidebar “Pathways of ATP Production,” two ATP molecules are
generated for each glucose molecule converted to two molecules of pyruvate.
The pyruvate then can be broken down further in the mitochondria in a set
of reactions collectively called the citric acid cycle. These reactions generate
NADH, which, as mentioned earlier, transfers electrons into the respiratory
chain, resulting in the release of enough energy to generate additional ATP
molecules.

Because the respiratory
chain requires oxygen, this pathway of ATP production is less prominent when
oxygen concentrations in the tissues are low. Instead, under low–oxygen
conditions, the largest proportion of ATP is produced during glycolysis (Berg
et al. 2002). This observation is supported by findings that, in the liver,
glycolysis occurs primarily in the perivenous region of the lobule, where
oxygen levels are lowest, even in the absence of alcohol (Jungermann and Thurman
1992). When oxygen levels in the liver tissues are too low, the immediate
breakdown products of glucose, including pyruvate, accumulate in the cells
because there is not enough oxygen available to further break down pyruvate
via the citric acid cycle (see the sidebar “Pathways of ATP Production”).
The accumulating pyruvate subsequently is converted to lactate, which also
can accumulate. In fact, the levels of lactate plus pyruvate are considered
a measure of glycolytic activity, particularly under hypoxic conditions, but
also when the tissues contain sufficient oxygen (Baio et al. 1998; Van Horn
and Cunningham 1999).

Researchers have measured
the levels of pyruvate and lactate in the livers of alcohol–consuming
animals to determine whether chronic alcohol consumption impairs glycolysis.
During these analyses, investigators found that the concentrations of lactate
plus pyruvate in the hepatocytes of alcohol–fed animals were lower than
in cells from control animals, which strongly suggests that chronic alcohol
consumption reduces glycolysis (Baio et al. 1998; Van Horn and Cunningham
1999). This effect occurred regardless of whether the cells were analyzed
immediately after they were removed from the animals or whether they were
first maintained in the presence of either normal or reduced oxygen levels.
These observations demonstrate that chronic alcohol consumption impairs glycolysis
in hepatocytes both in the presence and absence of oxygen. Moreover, the findings
suggest that the alcohol–related deficit in ATP concentrations observed
under low–oxygen conditions results not only from alcohol’s effects
on the respiratory chain but also from alcohol–related decreases in
glycolysis. Preliminary studies in which researchers directly measured ATP
concentrations in the cells indicate that hepatocytes of alcohol–consuming
animals produce significantly less ATP by glycolysis than do control animals.3
(3 Additional investigations have confirmed that the observed effects
did indeed result from reduced glycolysis rather than from the fact that the
alcohol–containing diets and control diets used in most studies differed
in the amounts of carbohydrates [e.g., glucose] they contained [Van Horn and
Cunningham 1999].)

One reason why glycolysis
is reduced in chronic alcohol users could be that the cells do not contain
enough of the starting material, glucose. Glucose can either be imported into
the hepatocyte from the blood by specific transport molecules located in the
hepatocyte membrane, or it can be generated inside the hepatocyte by breaking
down a very large molecule called glycogen, which serves as a storage form
of glucose in liver and other cells. Accordingly, reduced glycolysis could
be related to lowered cellular glucose uptake and/or glycogen breakdown. The
glucose transporter found in the membrane of hepatocytes in the perivenous
region is called Glut 1 (Van Horn et al. 2001). This molecule captures glucose
in the blood and moves it into the cells, where it is broken down to generate
energy or used to produce other compounds such as glycogen (Gumucio et al.
1996).4 (4 Hepatocytes in the periportal region of the
liver lobule, in contrast, actively produce new glucose, which then is exported
into the bloodstream primarily by a different glucose transporter molecule
called Glut 2.) Researchers have found that the numbers of Glut 1 molecules
on the hepatocytes are lower after chronic alcohol consumption (Van Horn et
al. 2001). This reduction could limit glucose uptake in perivenous hepatocytes
so that less glucose is available for glycolysis.

Reduced levels of glycogen
also could lead to reduced glucose availability and glycolysis in liver cells.
Various studies of the intact liver (Van Horn et al. 2001), whole liver hepatocytes
(Van Horn and Cunningham 1999; Van Horn et al. 2001), and periportal and perivenous
hepatocytes (Baio et al. 1998) demonstrated that glycogen levels are greatly
reduced in livers of chronic alcohol consumers. Researchers do not yet know
the exact reason why glycogen levels are lower after long–term alcohol
consumption. Studies have found that, in rats drinking alcohol, substantially
less glycogen is synthesized from the available glucose, probably because
the enzymes that generate glycogen from glucose are less active in alcohol
consumers. In the perivenous hepatocytes, the rate of glycogen synthesis also
may be lower because, as previously mentioned, these cells carry fewer molecules
of the Glut 1 transporter and therefore can take up less glucose from the
blood. (See Van Horn et al. 2001 for more details on the control of liver
glycogen concentrations in alcohol consumers.)

The observations discussed
in these sections suggest that the perivenous hepatocytes of alcohol consumers
experience more severe oxygen deficits, limiting the cells’ ability
to generate ATP in the mitochondrial respiratory chain. Therefore, these cells
would be particularly dependent on glycolysis to produce the ATP they need.
At the same time, however, less glucose is transported into the perivenous
hepatocytes, and less glycogen is available to these cells. As a result, glycolysis
and the associated ATP generation also would be reduced in the perivenous
hepatocytes. Because of these combined mechanisms, the perivenous hepatocytes
probably would be the first cells to experience ATP deficits and to show damage
resulting from the lack of this essential molecule—a hypothesis that
is consistent with the findings obtained when researchers studied liver tissues
of alcoholics.

Summary

Alcohol consumption enhances
the liver’s need for oxygen through several mechanisms. For example,
alcohol indirectly alters those metabolic events in the liver that are influenced
by oxygen levels. These alterations stem at least in part from increases in
the communication among cells and are mediated by cytokines and other stimulatory
agents that are released by activated Kupffer cells. In addition, the breakdown
of alcohol also uses up oxygen and therefore increases the oxygen needs of
liver cells. The increased demand for oxygen, in turn, can lead to oxygen
deficits at least in certain regions of the liver lobules (i.e., the perivenous
region).

Because ATP synthesis,
particularly in mitochondria, requires oxygen, oxygen deficits in the liver
can lead to reduced ATP production, with potentially detrimental effects to
cells. Indeed, studies indicate that ATP synthesis in the liver, both during
glycolysis and through the oxidative phosphorylation system, may be reduced
when liver tissue or isolated hepatocytes are subjected to low–oxygen
conditions. Accordingly, cells in the perivenous region of the liver lobule—which
are particularly likely to experience oxygen deficits following alcohol consumption—are
predisposed to show alcohol–related decreases in ATP levels. Reduced
ATP concentrations, in turn, could limit the cells’ ability to repair
damage caused by toxic byproducts of alcohol metabolism.

Taken together, the observations
described in this article lead to the following possible scenario: Alcohol
breakdown and other effects of alcohol on liver cells increase the cells’
need for oxygen. Higher oxygen consumption by some liver cells leads to oxygen
deficits in the environment of other liver cells, particularly perivenous
hepatocytes. As a result, these cells cannot maintain ATP levels adequate
for normal cell functioning and for the repair of alcohol–induced cell
damage. Insufficient amounts of ATP, in turn, predispose the perivenous cells
and the entire perivenous region of the lobule to tissue damage and the development
of alcoholic liver disease. Although this scenario has yet to be proven experimentally,
it is consistent with clinical observations demonstrating that the first signs
of alcoholic liver damage appear in the perivenous regions.

Acknowledgment

The authors acknowledge
the contributions of Priscilla Ivester and Tracey Young to many of the studies
reported in this review.